This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our understanding of the molecular basis of hair cell, sensory neuron and supporting cell development in the ear has seen dramatic progress. However, there is almost no basis for a molecular distinction between vestibular and cochlear histogenesis. Our preliminary data on Lmx1a null (Dreher) mice indicate a dramatic effect on the histogenesis of the basal as compared to the apical half of the organ of Corti: the former assumes a vestibular organ-like histogenesis whereas the latter develops a disturbed but recognizable organ of Corti phenotype. The present application will explore this finding to further our molecular understanding of organ of Corti-specific histogenesis. In Aim 1 we will characterize the Lmx1a null ear phenotype at the light- and electron microscopic level using in situ hybridization and immunohistochemistry to detect cell specific defects (e.g., SOX2, PROX1). In Aim 2 we will examine the Lmx1a expression pattern using ISH and expand our understanding of the molecular basis for the null phenotype by comparing the expression of genes generally considered important for cochlear development or uniquely expressed in the cochlea (Gata3, Fgf8, Fgf10). Finally, in Aim 3, we will employ a microarray approach to directly compare gene expression in the apical/basal cochlea and saccule of the Lmx1a null with that in wildtype littermates. These aims will provide new insight into the molecular basis of the vestibular organ-like phenotype of the basal cochlea of the Lmx1a mutant and, by extension, into the molecular basis of organ of Corti histogenesis. This understanding will be important in attempts to restore the organ of Corti from the flat epithelium of end-stage of cochlear degeneration.